Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.e., an antagonist of the melanocortin-4 receptor. The results of tests in acute and neuropathic pain models of the obtained compounds have shown that the type of linker used to connect pharmacophores had an effect on antinociceptive activity. Peptidomimetics containing longer flexible linkers were very effective at low doses in the neuropathic pain model. To elucidate the effect of linker lengths, two hybrids showing very high activity and two hybrids with lower activity were further tested for affinity for opioid (mu, delta) and melanocortin-4 receptors. Their complexes with the target receptors were also studied by molecular modelling. Our results do not show a simple relationship between linker length and affinity for particular receptor types but suggest that activity in neuropathic pain is related to a proper balance of receptor affinity rather than maximum binding to any or all of the target receptors.

The relationship between geopotential height and movement & landfall of tropical cyclone in the Bay of Bengal region

In this paper a simple relationship is employed to investigate relative impacts on the movement and landfall of tropical cyclone in the Bay of Bengal region when geopotential height of different troposphere levels is used as an input. Five tropical cyclone during pre-monsoon and post-monsoon season over the Bay of Bengal region has been selected for the study. The RS/RW data of coastal stations namely Kolkata (Dumdum), Dhaka, Agartala, Bhubaneswar, Visakhapatnam, Machlipatnam, Chennai and Karaikal has been collected for the period of the cyclones under study. The geopotential height of different standard levels has been plotted against the time for the stations for every cyclone. The study suggests that the cyclone moves towards and cross near the station having relatively steeper decrease in geopotential height upto mid tropical level followed by increased in geopotential height.

Question Difficulty Estimation Based on Attention Model for Question Answering

This paper addresses a question difficulty estimation of which goal is to estimate the difficulty level of a given question in question-answering (QA) tasks. Since a question in the tasks is composed of a questionary sentence and a set of information components such as a description and candidate answers, it is important to model the relationship among the information components to estimate the difficulty level of the question. However, existing approaches to this task modeled a simple relationship such as a relationship between a questionary sentence and a description, but such simple relationships are insufficient to predict the difficulty level accurately. Therefore, this paper proposes an attention-based model to consider the complicated relationship among the information components. The proposed model first represents bi-directional relationships between a questionary sentence and each information component using a dual multi-head co-attention, since the questionary sentence is a key factor in the QA questions and it affects and is affected by information components. Then, the proposed model considers inter-information relationship over the bi-directional representations through a self-attention model. The inter-information relationship helps predict the difficulty of the questions accurately which require reasoning over multiple kinds of information components. The experimental results from three well-known and real-world QA data sets prove that the proposed model outperforms the previous state-of-the-art and pre-trained language model baselines. It is also shown that the proposed model is robust against the increase of the number of information components.

Invertebrate DNA Methylation and Gene Regulation

BackgroundAs human activity alters the planet, there is a pressing need to understand how organisms adapt to environmental change. Of growing interest in this area is the role of epigenetic modifications, such as DNA methylation, in tailoring gene expression to fit novel conditions. Here, we reanalyzed nine invertebrate (Anthozoa and Hexapoda) datasets to validate a key prediction of this hypothesis: changes in DNA methylation in response to some condition correlate with changes in gene expression. ResultsWhile we detected both differential methylation and differential expression, there was no simple relationship between these differences. ConclusionIf changes in DNA methylation regulate invertebrate transcription, the mechanism does not follow a simple linear relationship.

Computational Fluid Dynamics Simulations of Mitral Paravalvular Leaks in Human Heart

In recent years, computational fluid dynamics (CFD) has been extensively used in biomedical research on heart diseases due to its non-invasiveness and relative ease of use in predicting flow patterns inside the cardiovascular system. In this study, a modeling approach involving CFD simulations was employed to study hemodynamics inside the left ventricle (LV) of a human heart affected by a mitral paravalvular leak (PVL). A simplified LV geometry with four PVL variants that varied in shape and size was studied. Predicted blood flow parameters, mainly velocity and shear stress distributions, were used as indicators of how presence of PVLs correlates with risk and severity of hemolysis. The calculations performed in the study showed a high risk of hemolysis in all analyzed cases, with the maximum shear stress values considerably exceeding the safe level of 300 Pa. Results of our study indicated that there was no simple relationship between PVL geometry and the risk of hemolysis. Two factors that potentially played a role in hemolysis severity, namely erythrocyte exposure time and the volume of fluid in which shear stress exceeded a critical value, were not directly proportional to any of the characteristic geometrical parameters (shape, diameters, circumference, area, volume) of the PVL channel. Potential limitations of the proposed simplified approach of flow analysis are discussed, and possible modifications to increase the accuracy and plausibility of the results are presented.

Invertebrate DNA methylation and gene regulation

As human activity alters the planet, there is a pressing need to understand how organisms adapt to environmental change. Of growing interest in this area is the role of epigenetic modifications, such as DNA methylation, in tailoring gene expression to fit novel conditions. Here, we reanalyzed nine invertebrate (Anthozoa and Hexapoda) datasets to validate a key prediction of this hypothesis: changes in DNA methylation in response to some condition correlate with changes in gene expression. While we detected both differential methylation and differential expression, there was no simple relationship between these differences. Hence, if changes in DNA methylation regulate invertebrate transcription, the mechanism does not follow a simple linear relationship.

Paleoenvironmental reconstruction of Triassic floras from the Central North Sea

The Triassic sediments of the Central North Sea (CNS) are considered to have been deposited in a continental environment under a semi-arid climate. The Skagerrak Formation in particular, comprises an alternation of sandstone and mudstone members, the development of which is considered to be climatically driven. However, conflicting models exist as to how climate influences member deposition. Here we analyse the climatic signal using a multivariate statistical approach in which de-trended correspondence analysis (DCA) is applied to palynological observations to quantify environmental reconstruction. Using DCA it has been possible to define paleoecological groups and construct a relative hydrological state trend showing hydrological conditions within the centre of the CNS basin during the Triassic. The resultant trends reveal that the relationship between hydrological conditions in the basin and the development of individual sandstones and mudstone members is perhaps not a simple as indicated by existing models. In particular our data suggest that whilst influenced by broader climate trends, in the basin centre, there is no simple relationship between climate change and sandstone/mudstone development. The data also indicates that the Julius and Jonathan mudstone members were deposited under differing hydrological conditions. The DCA trends shown here also suggest that the Carnian Pluvial Episode (CPE) documented from the South Permian Basin and Tethys is not expressed in the CNS.

Forward Looking Exporters

Economic textbooks outline a simple relationship between movements in a country’s exchange rate and its export volumes. When the exporter’s currency depreciates, export volumes are expected to increase due to competitiveness gains in foreign markets.

Linear Relationship of a Soil Total Water Potential Function and Relative Yield—A Technique to Control Salinity and Water Stress on Golf Courses and Other Irrigated Fields

A simple empirical approach is proposed for the determination of crop relative yield (%) through the soil total water potential (kPa). Recurring to decimal logarithms, from analytical exponential expressions, a linear simple relationship of soil total water potential Ψt (matric Ψm + potential Ψo) function and crop relative yield was studied and developed. The combination of the salinity model, the soil water retention model and the matric potential approach were used to reach this objective. The representation of turfgrass crop relative yield (%) versus a function of soil total water potential f(Ψt) values was shown through a log-normal graph (y = a + mx); the log scale axis “y” (ordinates) defines relative yield Yr, being two the origin ordinate “a” and “m” the slope; the normal decimal scale axis “x” (abscissa) is the function of soil total water potential f(Ψt). Hence, it is possible, using only two experimental points, to define a simple linear relation between a function of soil total water potential and crop relative yield, for a soil matric potential value lower than −20 kPa. This approach was first tested on golf courses (perennial turfgrass fields), but it was further decided to extend it to other annual crop fields, focused on the model generalization. The experimental plots were established, respectively, in Algarve, Alentejo and Oeiras (Portugal) and in the North Negev (Israel). Sprinkler and trickle irrigation systems, under randomized blocks and/or water and salt gradient techniques, were used for water application with a precise irrigation water and salt distribution. Results indicated that there is a high agreement between the experimental and the prediction values (R2 = 0.92). Moreover, the precision of this very simple and easy tool applied to turfgrass fields and other irrigated soils, including their crop yields, under several different sites and climatic conditions, can contribute to its generalization.

A curved manifold orients rotational dynamics in motor cortex

SummaryControlling arm movements requires complex, time-varying patterns of muscle activity 1,2. Accordingly, the responses of neurons in motor cortex are complex, time-varying, and heterogeneous during reaching 2–4. When examined at the population level, patterns of neural activity evolve over time according to dynamical rules 5,6. During reaching, these rules have been argued to be “rotational” 7 or variants thereof 8,9, containing coordinated oscillations in the spike rates of individual neurons. While these models capture key aspects of the neural responses, they fail to capture others – accounting for only 20-50% of the neural response variance. Here, we consider a broader class of dynamical models. We find that motor cortex dynamics take an unexpected form: there were 3-4 rotations at fixed frequencies in M1 and PMd explaining more than 90% of neural responses, but these rotations occurred in different portions of state space when movements differ. These rotations appear to reflect a curved manifold of fixed points in state space, around which dynamics are locally rotational. These fixed-frequency rotations obeyed a simple relationship with movement: the orientation of rotations in motor cortex activity were related almost linearly to the movement the animal made, allowing linear decoding of reach kinematic time-courses on single trials. This model constitutes a fundamentally novel way to consider pattern generation: like placing a record player in a large bowl, the frequency of activity is fixed, but the location of motor cortex activity on a curved manifold sets the orientation of locally-rotational dynamics. This system simplifies motor control, helps reconcile conflicting frameworks for interpreting motor cortex, and enables greatly improved neural decoding.